It is known that various lipid mediators such as eicosanoid and platelet activating factor (PAF) are produced by the activity of phospholipase from cell membranes.
Lysophosphatidic acid (hereinafter abbreviated as LPA) represented by

(wherein RA is acyl, alkenyl or alkyl) is a lipid which is produced from cell membranes, acts as a mediator for signal transduction and delivers various signals into cells. LPA that exists naturally is L-α-LPA.
Recently, the existence of three subtypes of LPA receptor has been disclosed and it is gradually proved that their physiological activities are via LPA receptor. Three subtypes of LPA receptor are called EDG (Endothelial differentiation gene)-2, 4 and 7, respectively, and form part of EDG receptor family as well as EDG-1, 3, 5, 6 and 8 that are sphingosine-1-phosphate receptor. EDG-2 is called LPA1 or VZG (Ventricular zone gene)-1, too (Mol Pharmacol 2000 December; 58(6) : 1188-96). LPA receptor to which LPA binds delivers signals into cells via G-protein coupled to the receptor. Gs, Gi, Gq are known as G-proteins that can bind to LPA receptor, and the receptors are said to relate to the response to the action of increase or, adversely, decrease of cell growth. Furthermore, since MAP-kinase systems operate in the downstreams of G-proteins, it has been known that LPA receptors deliver various signals.
Since localization of LPA receptors is different between their subtypes although they exist widely in living body, it is considered that the role of each receptor is different by the organ. The increase of blood pressure in rats, and the contraction of colon in rats and ileum in guinea pigs have been known as the pharmacological activity caused by LPA (J. Pharm. Pharmacol. 1991, 43, 774, J. Pharm. Pharmacol. 1982, 34, 514). In addition, the effect of LPA on urethral contraction is set forth in WO02/062389 specification and the suppressive effect of LPA on secretion of pancreatic juice is set forth in WO03/007991 specification.
In addition, concerning to the relationship between LPA and carcinoma, until now it is known that LPA enhances the proliferation of the epithelial cancer cells originated from prostate gland (J Cellular Physiol. 1998 174, 261) and ovarian cancer cells (J. Urol. 2000, 163, 1027).
In addition, it is known that LPA is related to the function of growth of various cells such as airway smooth muscle cells (Am. J. Physiol. Lung Cell Mol. Physiol., 2002, 282(1) : L91), fibroblast (Mol. Cell Biol., 1998, 18(12) : 7119), mesangial cells (Clin. Science 1999, 96, 431), hepatocyte, liver stellate cells (Biochem. Biophys. Res. Commun., 1998, 248, 436), vasucular smooth muscle cells (Am. J. Physiol., 1994, 267 (Cell Physiol. 36) : C204), vascular endothelial cells (Am. J. Physiol. Cell Physiol., 2000, 278(3) : C612), glia cells/Schwann cells (Proc. Natl. Acad. Sci. USA, 1999, 96, 5233), adipocytes (J. Clin. Invest., 1998, 101, 1431) as well as cancer cells. In addition, it is known that LPA is related to the function of chemotaxis of inflammatory cells as well as cancer cells besides cell growth (Biochem Biophys Res Commun., 1993, 15;193(2), 497). Moreover proliferation and cytokine-secreting activity in response to LPA of immune cells (J. Imuunol. 1999, 162, 2049), platelet aggregation activity to LPA (Biochem. Biophys. Res. Commun., 1981, 99, 391) are known. Besides, from analysis of knockout mouse of EDG-2 which is one of the LPA receptor, EDG-2 is concerned to be related to the brain function (Proc. Natl. Acad. Sci. USA, 2000, 97, 13384).
From these evidences, it is thought that drug antagonizing to LPA receptor is useful for prevention and/or treatment of diseases such as various kinds of disease namely urinary system disease, carcinoma-associated disease, proliferative disease, inflammation/immune system disease, disease by secretory dysfunction or brain-associated disease.
For example, for urinary system disease, symptom with prostatic hypertrophy or neurogenic bladder dysfunction disease (such as dysuria (micturation initiation delay, extension between on urination, urinary stream very small, intermission micturation, two steps of micturation), pollakiuria, night urination, urodynia), symptom to be caused by cerebrovascular disorder, Parkinson disease, cerebral oncosis, a multiple sclerosis, Shy-Drager symptom, spinal cord neoplasm, nucleous hernia, spinal canal stenosis, diabetes, etc. (such as dysuria (micturation initiation delay, extension between on urination, urinary stream very small, intermission micturation, two steps of miction), pollakiuria, night urination, urodynia), lower urinary tract symptom (for example, occlusion disease of lower urinary tract), inflammatory disease of lower urinary tract (such as infection), polyuria are thought about.
For example, for carcinoma-related disease, solid tumor, solid tumor metastasis, angiofibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leucemia are given. In solid tumor, mammary cancer, lung cancer, gastric cancer, carcinoma oesophagi, colon rectal cancer, liver cancer, ovarian cancer, theca cell tumor, androblastoma, cervix cancer, endometrial carcinoma, prostate cancer, kidney cancer, carcinoma cutaneum, osteosarcoma, pancreas cancer, urinary tract carcinoma, thyroid cancer, cerebral oncosis are given. In addition, it is thought that carcinomatous infiltration transition is suppressed by LPA receptor antagonist.
For example, for proliferative disease, the disease with aberrant angiogenesis are given (for example, re-arctation, diabetic retinopathy, angiogenesis-related glaucoma, crystalline lens fiber multiplication symptom, thyroid gland hyperplasia (including Basedow's goiter), lung inflammation, nephrotic syndrome and osteoporosis), and also artery obstruction, pulmonary fibrosis are given.
For example, for inflammation/immune system disease, psoriasis, nephropathy (for example, IgA nephropathy), nephritis by other inflammation/immunopathy, hepatitis, pneumonitis symptom are given.
For example, for disease by secretory dysfunction, secretory dysfunction by autonomic nervous system dysfunction is given, for example, Sjogren syndrome is given.
For example, for brain-related disease, brain infarction, cerebral apoplexy, brain or peripheral neuropathy are given.
In the specification of WO01/60819, it is described that the compound represented by formula (B)

[wherein R1B represents optionally substituted by alkyl, aryl, heterocyclic radical, alkyloxy, aryloxy, alkylthio, arylthio or halogen atom, R2B represents optionally substituted by alkyl, aryl, heterocyclic radical, alkyloxy, aryloxy or halogen atom, R3B represents hydrogen atom, lower alkyl or alkyl substituted by halogen atom, R4B represents a radical selected from (a) optionally substituted by phenyl, aryl or heterocyclic radical, (b) substituted or non-substituted alkyl or (c) substituted or non-substituted alkenyl, XB represents oxygen atom or sulfur atom. With the proviso that, R3B and R4B may form a five- to ten-membered cyclic structure together with a carbon atom to which they bind, and when R3B is a hydrogen atom, R4B represents a group other than methyl.]
or a salt thereof have the LPA receptor antagonistic activity.